From discovery to approval of an advanced therapy medicinal product-containing stem cells, in the EU

Abstract Background. Conjunctival epithelial stem cell therapy represents a potential and valuable therapeutic option for people suffering from conjunctival disorders. We recently developed a research protocol for the ex vivo cultivation of conjunctival epithelial cells. However, manufacturing and release of any Advanced Therapy Medicinal Product (ATMP) must be designed and planned according to the Good Manufacturing Practices (GMPs) guidelines. GMPs require the development and validation of properly defined manufacturing processes, analysis methods and process validations. Our previous experience with GMP-cultured corneal epithelial stem cells for clinical application on patients with limbal stem cell deficiency led us to set up a protocol for cultivation of conjunctival cells with standards complying with the requests for clinical studies. The major challenge for cell-based products is to develop manufacturing processes while maintaining the critical quality parameters in terms of safety, identity, purity and potency.Results. The manufacturing process was re-designed in order to include all the quality control assays needed for the release of any ATMP, i.e., sterility, morphology, cell viability, dose, cell identity and impurities, potency, lack of pyrogens, mycoplasma and viral detection. Methods and acceptance values were set for all the assays. Quality control assays to evaluate safety and efficacy were also investigated.Conclusion. Here, we describe the main phases of the manufacturing process of a conjunctival stem cell-based product to use in clinical applications. Such characterization is crucial for the preparation of documents and dossiers needed by the competent authorities to start a phase I clinical study on patients with conjunctival disorders. The procedure necessary to reach the marketing authorization of such a new cell-based product is still long, but, if reliable and validated, we believe that, in the near future, patients with conjunctival disorders might have a new treatment based on transplantation of autologous cultured conjunctival epithelial stem cells.

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Processing and Ex Vivo Expansion of Adipose Tissue-Derived Mesenchymal Stem/Stromal Cells for the Development of an Advanced Therapy Medicinal Product for Use in Humans

Cells ◽

10.3390/cells10081908 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1908

Author(s):

Anna Labedz-Maslowska ◽

Agnieszka Szkaradek ◽

Tomasz Mierzwinski ◽

Zbigniew Madeja ◽

Ewa Zuba-Surma

Keyword(s):

Adipose Tissue ◽

Medicinal Product ◽

Stromal Cells ◽

Manufacturing Process ◽

Cellular Therapy ◽

Ex Vivo ◽

Ex Vivo Expansion ◽

Advanced Therapy Medicinal Product ◽

Differentiation Potential ◽

Advanced Therapy

Adipose tissue (AT) represents a commonly used source of mesenchymal stem/stromal cells (MSCs) whose proregenerative potential has been widely investigated in multiple clinical trials worldwide. However, the standardization of the manufacturing process of MSC-based cell therapy medicinal products in compliance with the requirements of the local authorities is obligatory and will allow us to obtain the necessary permits for product administration according to its intended use. Within the research phase (RD), we optimized the protocols used for the processing and ex vivo expansion of AT-derived MSCs (AT-MSCs) for the development of an Advanced Therapy Medicinal Product (ATMP) for use in humans. Critical process parameters (including, e.g., the concentration of enzyme used for AT digestion, cell culture conditions) were identified and examined to ensure the high quality of the final product containing AT-MSCs. We confirmed the identity of isolated AT-MSCs as MSCs and their trilineage differentiation potential according to the International Society for Cellular Therapy (ISCT) recommendations. Based on the conducted experiments, in-process quality control (QC) parameters and acceptance criteria were defined for the manufacturing of hospital exemption ATMP (HE-ATMP). Finally, we conducted a validation of the manufacturing process in a GMP facility. In the current study, we presented a process approach leading to the optimization of processing and the ex vivo expansion of AT-MSCs for the development of ATMP for use in humans.

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Temporomandibular Joint Osteoarthritis: Regenerative Treatment by a Stem Cell Containing Advanced Therapy Medicinal Product (ATMP)—An In Vivo Animal Trial

International Journal of Molecular Sciences ◽

10.3390/ijms22010443 ◽

2021 ◽

Vol 22 (1) ◽

pp. 443

Author(s):

Robert Köhnke ◽

Marcus Oliver Ahlers ◽

Moritz Alexander Birkelbach ◽

Florian Ewald ◽

Michael Krueger ◽

...

Keyword(s):

Stem Cell ◽

Hyaluronic Acid ◽

Medicinal Product ◽

Temporomandibular Joint ◽

Stromal Cells ◽

Stromal Cell ◽

Advanced Therapy Medicinal Product ◽

Animal Trial ◽

Advanced Therapy ◽

Temporomandibular Joint Osteoarthritis

Temporomandibular joint osteoarthritis (TMJ-OA) is a chronic degenerative disease that is often characterized by progressive impairment of the temporomandibular functional unit. The aim of this randomized controlled animal trial was a comparative analysis regarding the chondroregenerative potency of intra-articular stem/stromal cell therapy. Four weeks after combined mechanical and biochemical osteoarthritis induction in 28 rabbits, therapy was initiated by a single intra-articular injection, randomized into the following groups: Group 1: AB Serum (ABS); Group 2: Hyaluronic acid (HA); Group 3: Mesenchymal stromal cells (STx.); Group 4: Mesenchymal stromal cells in hyaluronic acid (HA + STx.). After another 4 weeks, the animals were euthanized, followed by histological examination of the removed joints. The histological analysis showed a significant increase in cartilage thickness in the stromal cell treated groups (HA + STx. vs. ABS, p = 0.028; HA + ST.x vs. HA, p = 0.042; STx. vs. ABS, p = 0.036). Scanning electron microscopy detected a similar heterogeneity of mineralization and tissue porosity in the subchondral zone in all groups. The single intra-articular injection of a stem cell containing, GMP-compliant advanced therapy medicinal product for the treatment of iatrogen induced osteoarthritis of the temporomandibular joint shows a chondroregenerative effect.

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PNS136 Use of Real-World Evidence in Advanced Therapy Medicinal Product (ATMP) HTA Decisions

Value in Health ◽

10.1016/j.jval.2020.08.1580 ◽

2020 ◽

Vol 23 ◽

pp. S663

Author(s):

C. Watson ◽

G. Jones ◽

R. Miller

Keyword(s):

Medicinal Product ◽

Real World ◽

Advanced Therapy Medicinal Product ◽

Real World Evidence ◽

Advanced Therapy

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A practical approach for gmp-compliant validation of real-time PCR method for mycoplasma detection in human mesenchymal stromal cells as advanced therapy medicinal product

Biologicals ◽

10.1016/j.biologicals.2021.07.006 ◽

2021 ◽

Author(s):

V. Becherucci ◽

L. Curini ◽

R. Ceccantini ◽

S. Bisin ◽

V. Gori ◽

...

Keyword(s):

Medicinal Product ◽

Real Time ◽

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

Real Time Pcr ◽

Advanced Therapy Medicinal Product ◽

Human Mesenchymal Stromal Cells ◽

Mycoplasma Detection ◽

Advanced Therapy ◽

Pcr Method

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Development of Autologous Platelet-Rich Plasma Mixed-Microfat as an Advanced Therapy Medicinal Product for Intra-Articular Injection of Radio-Carpal Osteoarthritis: From Validation Data to Preliminary Clinical Results

International Journal of Molecular Sciences ◽

10.3390/ijms20051111 ◽

2019 ◽

Vol 20 (5) ◽

pp. 1111 ◽

Cited By ~ 4

Author(s):

Alice Mayoly ◽

Aurélie Iniesta ◽

Caroline Curvale ◽

Najib Kachouh ◽

Charlotte Jaloux ◽

...

Keyword(s):

Medicinal Product ◽

Platelet Rich Plasma ◽

Stromal Vascular Fraction ◽

Clinical Results ◽

Advanced Therapy Medicinal Product ◽

Validation Data ◽

Painful Condition ◽

Advanced Therapy ◽

Functional Scores

Wrist osteoarthritis (OA) is one of the most common conditions encountered by hand surgeons with limited efficacy of non-surgical treatments. The purpose of this study is to describe the Platelet-Rich Plasma (PRP) mixed-microfat biological characteristics of an experimental Advanced Therapy Medicinal Product (ATMP) needed for clinical trial authorization and describe the clinical results obtained from our first three patients 12 months after treatment (NCT03164122). Biological characterization of microfat, PRP and mixture were analysed in vitro according to validated methods. Patients with stage four OA according to the Kellgren Lawrence classification, with failure to conservative treatment and a persistent daily painful condition >40 mm according to the visual analog scale (VAS) were treated. Microfat-PRP ATMP is a product with high platelet purity, conserved viability of stromal vascular fraction cells, chondrogenic differentiation capacity in vitro and high secretion of IL-1Ra anti-inflammatory cytokine. For patients, the only side effect was pain at the adipose tissue harvesting sites. Potential efficacy was observed with a pain decrease of over 50% (per VAS score) and the achievement of minimal clinically important differences for DASH and PRWE functional scores at one year in all three patients. Microfat-PRP ATMP presented a good safety profile after an injection in wrist OA. Efficacy trials are necessary to assess whether this innovative strategy could delay the necessity to perform non-conservative surgery.

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